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Published OnlineFirst May 4, 2016; DOI: 10.1158/1078-0432.CCR-15-2709

CCR Drug Updates Clinical Cancer Research Talimogene Laherparepvec for the Treatment of Advanced Melanoma Patrick A. Ott1,2 and F. Stephen Hodi1,2

Abstract

Talimogene laherparepvec (T-VEC) is a ﬁrst-in-class oncolytic skin or lymph nodes. The drug is currently in clinical trials as virus that mediates local and systemic antitumor activity by direct monotherapy and in combination with immune-checkpoint inhi- cancer cell lysis and an "in situ vaccine" effect. Based on an increased bitors and radiotherapy in melanoma and other cancers. The durable response rate compared with granulocyte macrophage– mechanism of action, toxicity, and efﬁcacy as well as its role in colony stimulating factor in a randomized phase III trial, it was current clinical practice and potential future applications are approved by the FDA for the treatment of melanoma metastatic to reviewed. Clin Cancer Res; 22(13); 3127–31. 2016 AACR.

Introduction factor (GM-CSF) in the process. The genes encoding neuroviru- lence infected cell protein 34.5 (ICP34.5) and the infected cell Novel systemic treatment modalities such as inhibition of the protein 47 (ICP47) are functionally deleted in the virus, while the immune checkpoints CTLA-4 and PD-1/PD-L1 as well as BRAF gene for human GM-CSF is inserted. ICP34.5 is required for viral and MEK inhibition have expanded the range of therapeutic replication in normal cells, which is mediated by interaction with modalities for advanced melanoma (1–11). The antitumor activ- proliferating cell nuclear antigen (PCNA; ref. 14), whereas cancer ity of both MAPK pathway–targeted therapy (for BRAFV600- cells proliferate independently of ICP34.5 expression. ICP47 is mutant melanoma) and immune checkpoint inhibition (inde- critical for the evasion of HSV-infected cells from cytotoxic T cells pendent of a BRAF mutation) with response rates of 60% and by interfering with peptide processing and presentation on higher is striking and has improved the prognosis for many MHC-1 (15). Deletion of ICP47 in T-VEC prevents potentially patients. Both CTLA-4 and/or PD-1/PD-L1 blockade with mono- limited viral antigen presentation, which could compromise its clonal antibodies can achieve durable clinical benefit, suggesting function as an in situ vaccine. ICP47 deletion also leads to that endogenous tumor directed T-cell responses, suppressed by increased expression of the US11 gene, resulting in increased inhibitory pathways such as CTLA-4 and/or PD-1/PD-L1, can be virus replication in cancer cells without decreasing tumor selec- invigorated, resulting in effective tumor control (1, 2, 10–13). tivity. GM-CSF is a proinflammatory cytokine that promotes the Many patients experience primary or secondary resistance to PD-1 recruitment and maturation of dendritic cells (DC) as well as and/or CTLA-4 inhibition. Alternative treatments for these macrophages into potent antigen-presenting cells, leading to patients are therefore still urgently needed. Talimogene laherpar- priming of tumor-specific T cells (16). It has been used success- epvec (T-VEC), an agent with a different and potentially comple- fully as an immune adjuvant in many cancer vaccines. mentary mechanism of action to immune checkpoint blockade, is T-VEC has two distinct mechanisms of action: The lytic a recent addition to the therapeutic armamentarium for patients function of the virus destroys tumor cells directly, whereas the with advanced melanoma. lysis of the cancer cells leads to release of tumor antigens, virus, and GM-CSF, attracting DCs, thereby creating an in situ vaccine Mechanism of Action (Fig. 1). In a subcutaneous murine melanoma model, tumor T-VEC is an intralesionally delivered oncolytic immunotherapy growth inhibition on the contralateral, uninjected site was only comprised of a genetically engineered attenuated herpes simplex seen when T-VEC contained GM-CSF, establishing a systemic virus type 1 (HSV-1) of the JS-1 strain. T-VEC invades both effect of the lytic virus that is likely mediated by a host immune cancerous and healthy cells but can only replicate in cancer cells, response (17, 18). where it secretes granulocyte macrophage–colony stimulating Clinical Development Phase I 1Department of Medical Oncology, Melanoma Disease Center, and Center for Immuno-Oncology, Dana-Farber Cancer Institute, Harvard In a phase I study, 30 patients with previously treated mela- Medical School, Boston, Massachusetts. 2Department of Medicine, noma, breast cancer, gastric adenocarcinoma, or head and neck Brigham and Women's Hospital, Boston, Massachusetts. cancer who had cutaneous or subcutaneous lesions accessible Corresponding Author: Patrick A. Ott, Melanoma Disease Center & Center for for injections were treated with different doses and schedules Immuno-Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Bos- of T-VEC (19). The most common adverse events were grade 1 ton, MA 02215. Phone: 617-582-9030; Fax: 617-632-6727; E-mail: fever, constitutional symptoms, nausea, anorexia, and injec- [email protected] tion site reactions. One patient was reported to experience doi: 10.1158/1078-0432.CCR-15-2709 grade 2 fever, rigor, hypotension, tachycardia, and constitu- 2016 American Association for Cancer Research. tional symptoms. Overall, the toxicities were more intense in

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Dendritic cells Figure 1. In situ vaccination effect of T-VEC, potentially converting a non–T-cell- inflamed tumor to a T-cell–inflamed T-VEC Lysed tumor tumor. Replication of T-VEC in tumor cells cells leads to their lysis with release of tumor antigens, viral antigens and pathogen-associated molecular Inflammatory patterns (viral DNA, RNA, and cytokines T cells proteins), and GM-CSF. This process (IFNγ, TNFβ) results in the recruitment and Noninflamed GM-CSF Inflamed maturation of antigen-presenting cells, “cold” tumor “hot” tumor including dendritic cells, which present tumor antigens to cytotoxic CD8 T cells. © 2016 American Association for Cancer Research

HSV-seronegative patients; an initial low dose of T-VEC, lead- was administered until CR, clinically significant progressive dis- ing to HSV seroconversion, followed by a series of higher-dose ease, intolerable side effects, or 12 months of therapy without an injections was better tolerated. There were no partial or com- objective response. As in the phase II study, T-VEC was initially plete responses (CR); however, flattening of both injected administered at 106 pfu/mL for seroconversion, whereas subse- and noninjected metastases was seen in 6 of 26 evaluable quent doses were given at 108 pfu/mL 3 weeks after the first dose patients. Posttreatment biopsies of injected lesions showed and then every 2 weeks. T-VEC injection was restricted to cuta- inflammation and necrosis. neous and subcutaneous metastases; different lesions could be prioritized for injection differently at any visit depending on its size and the emergence of new lesions. GM-CSF was given daily Phase II subcutaneously at 125 mg/m2 during the first 14 days of a 28-day Fifty patients with unresectable stage IIIC–IV melanoma with cycle; it was chosen as a comparator arm based on overall survival one or more injection-accessible tumor lesions were enrolled (OS) benefit compared with historical controls observed in a in a phase II study assessing the response rate, survival, and safety previous study in melanoma patients at high risk for recurrence of T-VEC (20). Thirty-seven (74%) of the patients had received (23). The primary endpoint was durable response rate (DRR), prior systemic therapy and 20 (40%) had M1c visceral disease. defined as PR or CR with an onset during the first 12 months of Based on the experience from the phase I study, patients received treatment and lasting for at least 6 months. Secondary endpoints intratumoral injections of up to 4 mL of 106 pfu/mL of T-VEC, included OS, best overall response, and duration of response. followed 3 weeks later by up to 4 mL of 108 pfu/mL, and Approximately half of the patients in each arm were previously subsequently every 2 weeks for a maximum of 24 treatments. In untreated; 45% of patients in the T-VEC arm and 39% of patients a small subset of patients, peripheral blood and tumor biopsies þ þ in the GM-CSF arm were stage IVM1b/c. The study met its primary were obtained for assessment of effector T cells, CD4 FoxP3 þ þ endpoint: DRR was significantly higher in the T-VEC arm (16.3%) regulatory T cells (Treg), CD8 FoxP3 suppressor T cells, and compared with the GM-CSF arm (2.1%). The overall response rate myeloid-derived suppressive cells (MDSC; ref. 21). Eight CRs and was also significantly increased in the T-VEC arm (26.4%) com- five partial responses (PR) were observed, resulting in an overall pared with GM-CSF alone (5.7%) as was the number of CRs response rate (ORR) of 26%. Twelve of the 13 responses lasted (10.8% vs. 1%). The median OS was 23.3 months in the T-VEC longer than 6 months. Compared with untreated melanoma arm and 18.9 months in the GM-CSF arm (HR, 0.79; 95% CI, lesions, melanoma metastases regressing after treatment with 0.62–1.00; P ¼ 0.051), and it was therefore unclear, at least from T-VEC exhibited an increase of MART-1–specific T cells compared the primary study analysis, whether T-VEC was associated with with melanoma lesions from untreated patients, whereas num- improved OS. bers of Tregs and MDSCs were decreased. Evidence for increased Subgroup analyses showed higher antitumor activity of T-VEC MART-1–specific T cells was seen in tumor-infiltrating lympho- in patients with stage IIIB, IIIC, and IVM1a disease: with T-VEC, cytes (TIL) and peripheral blood from a patient with a CR after T- DRR was 33% in patients with IIIB or IIIC and 16% in patients TVEC, suggesting the induction of a systemic melanoma-specific with stage IVM1a, respectively compared with 0% and 2% with immune response. Consistent with the observations in the phase I GM-CSF. In contrast, DRR was 3% and 7% in patients with study, T-VEC was overall well tolerated with low-grade constitu- stage IVM1b and M1c disease who received T-VEC, compared tional symptoms, injection site reactions, and gastrointestinal with 4% and 3% in patients who received GM-CSF. Furthermore, symptoms as the most commonly observed adverse events. the improved efficacy of T-VEC over GM-CSF was predominantly seen in treatment-na€ve patients. Phase III The treatment was overall well tolerated: the most common In a phase III study, 436 patients with unresected stage IIIB/IV toxicities included injection site reactions, fatigue, chills, and fever melanoma were randomized at a 2:1 ratio to receive T-VEC versus and were in line with previous experience from phase I and II subcutaneously administered GM-CSF (22). T-VEC or GM-CSF trials. The only 3 toxicity that occurred in 2% of patients was

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Talimogene Laherparepvec in Melanoma

Table 1. Ongoing clinical trials of talimogene laherparepvec across tumor types Phase N Tumor type Disease setting Design Primary endpoint Treatment Sponsor ClinicalTrials.gov ID II 61 Melanoma Unresectable stage IIIB/C, IV One arm T-VEC DNA in blood T-VEC Amgen NCT02014441 and urine I, II 219 Melanoma Unresectable stage IIIB/C, IV Two arms, Safety, ORR T-VECþ/ Amgen NCT01740297 randomized ipilimumab II 150 Melanoma Neoadjuvant stage IIIB/C, IVM1a One arm RFS T-VEC Amgen NCT02211131 Ib, III 660 Melanoma Unresectable stage IIIB/C, IV Two arms, Safety, DLT, PFS, OS T-VECþ/ Amgen NCT02263508 randomized pembrolizumab II 110 Melanoma Unresectable stage IIIB/C, IV One arm Correlation CD8 T-VEC Amgen NCT02366195 cells/ORR II 35 Inﬂammatory Inoperable recurrence One arm DCR T-VEC MD Anderson NCT02658812 breast cancer Cancer Center Ib 40 SCCHN Recurrent/metastatic One arm Safety, DLT T-VEC þ Amgen, Merck NCT02626000 pembrolizumab I 100 HCC, liver Not candidate for curative- One arm Safety, DLT T-VEC Amgen NCT02509507 metastases intent treatment Ib, II 32 Sarcoma Neoadjuvant One arm Safety, pCR T-VEC þ radiation University NCT02453191 of Iowa Abbreviations: DCR, disease control rate (CRþPRþSD); DLT, dose-limiting toxicity; HCC, hepatocellular carcinoma; ORR, overall response rate; pCR, pathologic response rate; PFS, progression-free survival; RFS, recurrence-free survival; SCCHN, squamous cell carcinoma of the head and neck.

cellulitis; other grade 3 or 4 toxicities included fatigue, extremity of another drug with an entirely different mechanism of action is pain, vomiting, injection site pain, edema, and extremity pain. No welcome, both for standard-of-care treatment and current as well deaths were attributed to either of the study drugs. This adverse as future investigations. event profile compares favorably with toxicities after CTLA-4 and/ Given T-VEC's benign toxicity profile, the durability of tumor or PD-1 pathway inhibition. responses, the requirement for the presence of skin metastases, Limitations of the study, which was designed and initiated and the efficacy in stage IIIB, IIIC, and IVM1a disease, the drug prior to the widespread availability of immune checkpoint appears to be an attractive choice for (i) "slow-growing" lymph inhibitors and BRAF/MEK inhibitors for patients with advanced node, in-transit or distant skin metastases, e.g., patients who had melanoma, include the choice of the comparator arm (GM- several resections in the past and are no longer deemed resectable; CSF), the complexity of the measurements assessing the pri- (ii) BRAF wild-type patients who have unequivocally progressed mary endpoint involving many modalities (clinical assess- on PD-1 and/or CTLA-4 inhibition; and (iii) BRAF wild-type ments, radiography, and biopsies), and the small number and patients with multiple comorbidities or autoimmune disease size of baseline lesions in a subset of the patients. A perceived who are not deemed good candidates for immune checkpoint ineffectiveness of GM-CSF (known to have modest, if any, inhibition. Since the drug is a live, genetically engineered virus single-agent antitumor activity in melanoma) may have led to that actively replicates in the host, special attention needs to be differential decisions about continuation of treatment in the given with regard to health care provider and patient education, two treatment arms. These concerns seem to be supported by transmission precautions, and environmental safety. the fact that 58.3% of patients in the T-VAC arm discontinued fi treatment prior to the protocol-speci ed24weeksascompared Current and Future Clinical Development with 75.1% in the control arm and only 1.4% never received treatment in the T-VEC arm as compared with 9.9% in the GM- Multiple clinical trials are ongoing assessing T-VEC in mela- CSF arm. These potential biases were nevertheless deemed noma in the neoadjuvant setting as well as in the metastatic setting unlikely to affect the statistically robust difference in DRR (the with a focus on correlative studies such as analysis of talimogene primary endpoint), and T-VEC was approved by the FDA for the laherparepvec DNA in blood and urine as well as T-cell tumor treatment of advanced melanoma in October 2015. infiltration prior to and after treatment. T-VEC is also studied as monotherapy in advanced head and neck, inflammatory breast T-VEC in Current Clinical Practice for cancer, and hepatocellular cancer and in combination with radiation in the neoadjuvant setting of sarcoma (Table 1). From a Advanced Melanoma clinical development perspective, the main attraction of T-VEC Substantial improvements have been made in the treatment of may be its potential as a combinatorial agent partnering with advanced melanoma in recent years. BRAF and combined BRAF/ checkpoint inhibition. In this regard, its role as an in situ vaccine is MEK inhibition (in BRAFV600-mutant melanoma) and CTLA-4 particularly attractive. Immune checkpoint inhibition given by and PD-1 inhibition have all shown improved OS in advanced itself may be limited by the size and specificity of preexistent melanoma. Combined PD-1/CTLA-4 inhibition has demonstrat- tumor-specific T-cell responses that are generated by physiologic ed improved PFS and a RR of 60%, independent of BRAFV600 interaction of the evolving tumor and the host immune system. In status. While T-VEC was developed and the registration trial nonresponders to immune checkpoint inhibition, it is possible OPTIM-3 designed and largely conducted in a "pre-checkpoint that there is insufficient priming of tumor-specific T-cell clones— inhibition, pre-MAPK pathway inhibition era," the recent FDA and, as a result, the critical threshold of T cells necessary to trigger approval places the drug in a vastly different therapeutic land- an immune infiltrate is not reached. Although traditional peptide scape for advanced melanoma. Nevertheless, despite the avail- vaccines targeting native antigens such as gp100 and MART-1, ability of a number of effective drugs for melanoma, the approval given with incomplete Freund's adjuvant, have not provided

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synergy with CTLA-4 or PD-1 inhibition in advanced melanoma vaccines and immune checkpoint blockade in mouse models, (13, 24), T-VEC (and other novel vaccines) may provide the combinatorial strategies with CTLA-4 and or PD-1/PD-L1 inhi- necessary stimulation to broaden the repertoire of T cells engaged bition are being developed. in the antitumor response. In support of this hypothesis, synergy of CTLA-4 and PD-1 inhibition with the whole tumor cell vaccines Conclusions GVAX (autologous tumor þ GM-CSF), FVAX (autologous tumor T-VEC is a first-in-class recombinant attenuated oncolytic HSV- þ Flt3 ligand), and TEGVAX (autologous tumor þ GM-CSF þ 1 virus encoding GM-CSF. In phase I–III trials, the drug has TLR4 and TLR 7/8 agonists) was demonstrated in the mouse B16 demonstrated a favorable toxicity profile and was associated with melanoma model (25, 26). Both CTLA-4 and PD-1 inhibition also durable objective responses in patients with unresectable stage III showed synergy with a novel material-engineered scaffold vaccine and IV melanoma, leading to its FDA approval in this disease. The that codelivers autologous tumor lysate, GM-CSF, and the TLR-9 dual mechanism of action (direct cell killing and in situ vaccine agonist CPG with precise spatial and temporal control (27). effect) is novel and distinct from those of other agents in the Recently reported preliminary efficacy data from an ongoing study growing landscape of immuno-oncology drugs. Initial data on the combining T-VEC and the anti-CTLA antibody ipilimumab combination of T-VEC with CTLA-4 inhibition in advanced appear to support synergy between the two agents: 10 of 17 melanoma are promising and provide evidence in humans that evaluable patients (56%) had an objective response, including the combination of a cancer vaccine and immune checkpoint 6 CRs and 4 PRs, which is substantially higher than what would be blockade may be synergistic. Given this potential synergy and expected from either of the drugs alone (28). The combination of the relatively modest antitumor activity as a single agent (at T-VEC and the PD-1 inhibitor pembrolizumab is under way in least in melanoma), T-VEC is a potentially attractive partnering melanoma and head and neck cancer (Table 1). agent for combinatorial immunotherapy approaches; it is cur- Multiple lines of evidence indicate the importance of neoanti- rently in development in combination with CTLA-4 and PD-1 gens as immunogenic tumor-specific antigens. Neoantigens are blockade as well as radiotherapy. In light of the increasing encoded by somatic mutations in tumor cells, resulting in pep- evidence that immune checkpoint blockade is mainly effective tides with amino acid changes that can be presented to T cells by in patients with a preexisting T-cell–inflamed tumor microen- personal HLA molecules. Because neoantigens are not exposed to vironment, T-VEC—along with other approaches that have the central tolerance in the thymus, they should be strongly immu- potential to mediate tumor-directed T-cell priming and traf- nogenic. This assumption is supported by the recently documen- ficking into the tumor, such as vaccines—may become an ted association of clinical benefit from immune checkpoint increasingly important tool for cancer immunotherapy. blockade in patients with melanoma, non–small cell lung cancer, and colorectal cancer (29–31); the detection of neoantigen-specific T cells in cancer patients treated with immune checkpoint Disclosure of Potential Conflicts of Interest blockade and TIL therapy, and the antitumor activity of neoanti- P.A. Ott is a consultant/advisory board member for Alexion, Amgen, and gen-specific TILs (32), among other evidence. Tumor antigens Bristol-Myers Squibb. F.S. Hodi is a consultant/advisory board member for fl released through the cytolytic effect of T-VEC may contain neoan- Amgen, Genentech, Merck, and Novartis. No other potential con icts of interest were disclosed. tigens. Therefore, the in situ vaccination effect of T-VEC may lead to priming of T cells with neoantigens. The availability of neoantigen discovery pipelines using next-generation sequencing to Authors' Contributions identify somatic tumor mutations and neural network/machine Conception and design: P.A. Ott, F.S. Hodi learning-based algorithms to predict binding of peptides to Development of methodology: P.A. Ott HLA class I now enables the design of vaccines specifically Analysis and interpretation of data (e.g., statistical analysis, biostatistics, computational analysis): P.A. Ott, F.S. Hodi directed at neoantigens. A neoantigen peptide vaccine has recently fi Writing, review, and/or revision of the manuscript: P.A. Ott, F.S. Hodi shown striking ef cacy in a mouse sarcoma model (33, 34). Study supervision: P.A. Ott, F.S. Hodi Clinical trials using a personalized neoantigenic peptide vaccine in high-risk melanoma and glioblastoma (NCT01970358 and Received February 17, 2016; revised April 6, 2016; accepted April 7, 2016; NCT02287428) are ongoing. In light of the synergy between published OnlineFirst May 4, 2016.

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www.aacrjournals.org Clin Cancer Res; 22(13) July 1, 2016 3131

Talimogene Laherparepvec for the Treatment of Advanced Melanoma

Patrick A. Ott and F. Stephen Hodi

Clin Cancer Res 2016;22:3127-3131. Published OnlineFirst May 4, 2016.

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